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Published on: December 28, 2017
Persistent Candida albicans colonization and molecular mechanisms of azole resistance in autoimmune
Emilia Siikala1, Riina Rautemaa, Malcolm Richardson
1Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland. emilia.siikala@helsinki.fi
Objectives:
Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I) suffer from chronic candidosis caused mainly by Candida albicans, and repeated courses of azole antifungals have led to the development of resistance in the APECED patient population in Finland. The aim of our study was to address whether the patients are persistently colonized with the same or genetically closely related strains, whether epidemic strains are present and which molecular mechanisms account for azole resistance.
Methods:
Sets of C. albicans (n = 19) isolates from nine APECED patients reported with decreased susceptibility to fluconazole isolated up to 9 years apart were included. The strains were typed by multilocus sequence typing. CDR1/2, MDR1 and ERG11 mRNA expression was analysed by northern blotting and Cdr1, Cdr2 and Mdr1 protein expression by western blotting, and TAC1 and ERG11 genes were sequenced.
Results:
All seven patients with multiple C. albicans isolates analysed were persistently colonized with the same or a genetically closely related strain for a mean of 5 years. All patients were colonized with different strains and no epidemic strains were found. The major molecular mechanisms behind the azole resistance were mutations in TAC1 contributing to overexpression of CDR1 and CDR2. Six new TAC1 mutations were found, one of which (N740S) is likely to be a gain-of-function mutation. Most isolates were found to have gained multiple TAC1 and ERG11 point mutations.
Conclusions:
Despite clinically successful treatment leading to relief of symptoms, colonization by C. albicans strains is persistent within APECED patients. Microevolution and point mutations occur within strains, leading to the development of azole-resistant isolates.
Insights
Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) are persistently colonized by Candida albicans. Azole resistance develops through mutations in TAC1 and ERG11 genes, leading to microevolution of fungal strains.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Genetics
Background:
- Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients experience chronic Candida albicans infections.
- Repeated azole antifungal treatments have led to azole-resistant Candida strains in APECED patients.
Purpose of the Study:
- To investigate persistent Candida albicans colonization in APECED patients.
- To identify epidemic strains and molecular mechanisms of azole resistance.
Main Methods:
- Multilocus sequence typing of 19 Candida albicans isolates from 9 APECED patients.
- Analysis of CDR1/2, MDR1, and ERG11 gene expression and protein levels.
- Sequencing of TAC1 and ERG11 genes for mutations.
Main Results:
- Persistent colonization by the same or closely related Candida albicans strains was observed in 7 patients for a mean of 5 years.
- No epidemic strains were identified; each patient was colonized by distinct strains.
- Azole resistance was primarily linked to TAC1 mutations causing CDR1/CDR2 overexpression, with six new TAC1 mutations discovered.
Conclusions:
- Candida albicans colonization persists in APECED patients despite successful treatment.
- Microevolution and point mutations within Candida albicans strains contribute to the development of azole resistance.
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